Substance abuse is one of the most common health disorders in US veterans. Of the over million opiate- dependent subjects today, less than a quarter of such individuals receive treatment. Pharmacotherapeutic approaches have traditionally targeted 5 opioid receptors since heroin and its metabolites bind with highest affinity to this receptor subtype. Treatment strategies such as methadone have improved substance abuse outcomes, but they do not effectively block opiate craving and thus are still associated with high rates of relapse. Using a strategy of indirectly regulating neural systems to modulate opioid-related behavior, our preclinical rat pilot studies (using a drug self-administration paradigm) consistently demonstrated that cannabidiol (CBD), a nonpsychoactive component of cannabis, specifically inhibits cue-induced heroin-seeking behavior. CBD's selective effect on cue-induced heroin- seeking behavior was pronounced after 24 hours and endured even two weeks after the last drug administration following short-term CBD exposure. The fact that drug seeking is generally triggered by exposure to conditioned cues suggests that CBD might be an effective treatment for heroin relapse, specially given its protracted impact on behavior. The overall aim of this project is to understand the potential role of CBD as a treatment for drug craving. To this end, the experiments outlined in this application will: (1) Identify the specific relapse condition sensitive to CBD. Although our preliminary findings showed that CBD specifically attenuated drug-seeking behavior associated with environmental cues, but not heroin prime, factors such as stress can also trigger relapse. We will evaluate the effect of CBD on drug-seeking induced by mild footshock stress in animals with moderate and extended access heroin self-administration history. (2) Examine the effects of CBD in methadone-maintained subjects in relation to heroin-seeking behavior. Methadone is the most common pharmacological treatment for opioid abuse available today for US veterans, but it does not effectively reduce craving. It is thus important to evaluate whether CBD would be an effective adjunct treatment in methadone-maintained subjects. (3) Obtain insight as to the neurobiology underlying CBD effects on heroin-seeking behavior. Postmortem molecular and biochemical studies will be conducted on markers linked to cannabinoid, glutamate and dopamine systems in mesocorticolimbic brain regions of animals in which drug relapse behavior has been characterized. Given the important role of glutamatergic and dopaminergic transmission in drug addiction vulnerability, in vivo microdialysis will also be used to directly monitor dynamic fluctuations of glutamate and dopamine levels during active drug seeking behavior. This investigation, together with complementary clinical investigation on the role of CBD on drug craving, has the potential to significantly impact the development of a novel agent for relapse prevention that is critical for preventing the continued cycle of drug abuse.